What Would the Nurse Teach to the Postpartum Mother Before Administering the Rho(D) Immune Globulin

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PLoS One. 2020; fifteen(iii): e0230073.

Clinical value of unlike anti-D immunoglobulin strategies for preventing Rh hemolytic disease of the fetus and newborn: A network meta-analysis

Xiaohui Xie, Data curation, Formal assay, Resources, Software, Writing – original draft, Writing – review & editing,^{# 1} Qiurong Fu, Information curation, Resource,^{# 2} Ziwei Bao, Resources, Writing – review & editing,^{# 3} Yi Zhang, Formal assay, Investigation, Software, Writing – original draft, Writing – review & editing,^{iv, *} and Dan Zhou, Formal analysis, Resource, Software, Writing – original typhoon, Writing – review & editing ^{ane, *}

Xiaohui Xie

^ane Department of Obstetrics and Gynecology, the First People's Hospital of Neijiang, Neijiang, Sichuan Province, P. R. Mainland china

Qiurong Fu

² Section of Nursing, The first Affiliated Hospital of Hainan Medical University, Haikou, Hainan Province, P. R. Cathay

Ziwei Bao

³ Department of medicine, Southwest Medical University, Luzhou, Sichuan Province, P. R. Mainland china

Yi Zhang

⁴ Department of General Surgery, the First People'southward Hospital of Neijiang, Neijiang, Sichuan Province, P. R. China

Dan Zhou

ⁱ Department of Obstetrics and Gynecology, the Offset People'southward Hospital of Neijiang, Neijiang, Sichuan Province, P. R. Communist china

Frank T. Spradley, Editor

Received 2019 Sep two; Accepted 2020 Feb twenty.

Supplementary Materials

S1 Checklist: PRISMA NMA checklist of Items to include when reporting a systematic review involving a network meta-analysis. (DOCX)

GUID: 916465D2-17DB-4902-8064-C8D9B833905A

S1 Table: The raw data of all included studies. (XLSX)

GUID: 98199483-56FC-477D-BD3A-DE871BDC0647

Attachment: Submitted filename: Response to Reviewers.doc

GUID: 9565521E-B9F6-4F04-BEA0-D6B3C8273987

Attachment: Submitted filename: Response to Reviewers.medico

GUID: 744B102D-E60C-4D8C-AF1F-F8E8791E40F5

Data Availability Statement

All relevant information are within the manuscript and its Supporting Information files.

Abstract

Background

Several anti-D immunoglobulin strategies exist for preventing Rh hemolytic illness of the fetus and newborn. This study systematically assessed the clinical value of those therapeutic strategies.

Methods

The Web of Scientific discipline, PubMed, EMBASE, China National Knowledge Infrastructure (CNKI) and Wanfang databases were searched for eligible studies that evaluated the value of unlike anti-D immunoglobulin strategies in preventing maternal anti-D antibody sensitization. Combined odds ratios (ORs) and their 95% conviction intervals (CIs) were calculated. The network meta-analysis was conducted using Stata 14.2 and WinBUGS 1.4.3 software.

Results

Xx-four original studies involving 64860 patients were included. Among all therapeutic measures, injecting 300 μg anti-D immunoglobulin at 28 and 34 gestational weeks (antenatal 5/E) appeared to be the virtually effective measure out for preventing maternal antibody sensitization (surface nether the cumulative ranking curve [SUCRA] = 96.8%), while a single injection at 28 gestational weeks (SUCRA = 89.2%) was the second most effective. Administering no injection or a placebo (SUCRA = 0.0%) was the least constructive intervention measure out.

Conclusion

Among the therapeutic measures, antenatal 5/E appeared to be the all-time method for reducing the positive incidence of anti-D antibodies in the maternal serum; thus, it may be the nearly effective treatment for preventing fetal hemolytic disease.

Introduction

Hemolytic disease of the fetus and newborn (HDFN) can lead to fetal hemolytic anemia, jaundice, intellectual retardation, premature nativity, abortion and stillbirth. HDFN is an important crusade of neonatal morbidity and death [ane–3]. To reduce the incidence of HDFN and mortality among fetuses and neonates, anti-D immunoglobulin has been tested in clinical trials in the Great britain and Usa since the 1960s. Anti-D immunoglobulin has been used to prevent postpartum disease in RhD-negative women and has greatly reduced HDFN-related morbidity equally well as fetal and neonatal mortality [4]. The anti-D antibody production charge per unit in the maternal serum afterward immunization has also decreased significantly from 12–13% to approximately 1.ii%. Prenatal prophylaxis with anti-D immunoglobulin in Rh-negative mothers can further reduce anti-D antibody production in maternal sera, which has further reduced the incidence of hemolytic diseases in fetuses and newborns since 1980 [five–11].

Notwithstanding, multiple countries recommend various anti-D immunoglobulin injection schemes, and no consensus has been reached on the utilize of anti-D immunoglobulin worldwide. Routine prenatal anti-D prophylaxis (RAADP) is recommended in some countries, while postpartum anti-D immunoglobulin injections are notwithstanding used in other countries. Furthermore, the injection dose differs in some countries due to the lack of bachelor immunoglobulin. Lee et al. suggested that administering depression doses of anti-D immunoglobulin (50 μg) provided no benefit [12]. Still, excessive doses may increase the adventure of allergic reactions and infectious diseases.

Until now, no meta-analysis has been conducted to evaluate the clan between anti-D antibody production rates in the maternal serum and various therapeutic strategies regarding anti-D immunoglobulin. Nosotros conducted this study to systematically evaluate the preventive furnishings of anti-D immunoglobulin on HDFN via network meta-analysis based on all related published data.

Fabric and methods

Search strategy

A comprehensive search strategy was employed to search the PubMed, EMBASE, Web of Scientific discipline, Prc National Knowledge Infrastructure (CNKI) and Wanfang databases. The latest search was conducted on 7 July 2019. The post-obit keywords were used in accordance with the search strategy: "RhD-negative" OR "D-negative" OR "Rh(D) Immuno-Globulin" OR "Anti-D Immunoglobulin" OR "Anti-D Antibody" OR "the hemolytic disease of the newborn" OR "haemolytic illness of the newborn" OR "HDFN" et al.

Inclusion and exclusion criteria

The inclusion criteria were every bit follows: 1) randomized controlled studies on administering anti-D immunoglobulin injections to RhD-negative pregnant women; 2) Rh-positive fetuses in intrauterine pregnancies of Rh-negative pregnant women; iii) reported dose and frequency of anti-D immunoglobulin injections; and 4) reported positive incidence of anti-D antibiotic in postpartum mothers. Duplications, reviews, case reports, conference abstracts, and studies without useful information were excluded.

Study option

Ii authors (XXH and FQR) screened the abstracts and titles of eligible publications and judged whether to further review the full text independently. Nosotros contacted the trial author when full texts were unavailable. Total texts were independently reviewed past XXH and ZD. In the case of whatsoever disagreement during the selection procedure, the decisions were obtained after group give-and-take. Finally, we used flow chart to show the total number of retrieved references and the number of included and excluded studies.

Data extraction

Two investigators nerveless data independently in accordance with predesigned tables, which included the name of the kickoff writer, publication year, country, sample size, intervention measures, control measures, and anti-D antibiotic production rate in the maternal serum.

Two researchers independently assessed the quality of all included studies using the Newcastle-Ottawa quality assessment scale (NOS). This method comprised three parameters of quality: selection (score: 0–4), comparability (score: 0–2), and upshot assessment (score: 0–3), with total scores ranging from 0–9. NOS scores >6 were considered to betoken high-quality studies.

Statistical analysis

Stata statistical software, version xiv.ii and WinBUGS ane.4.3 were practical to analyze the relationship between anti-D antibody product rates in the maternal serum and diverse anti-D immunoglobulin injection regimens. The random-effects model with vague priors for multiarm trials was used. The model parameters were estimated using the Markov chain Monte Carlo method of Gibbs sampling. The results are reported every bit the odds ratio (OR) and standardized mean deviation(SMD) with 95% confidence intervals (CIs). To evaluate the inconsistency between direct and indirect effect estimates for the same comparisons, nosotros evaluated each closed loop in the network. In a closed loop, we employed the inconsistency factor (IF) to evaluate heterogeneity among the included studies. Node analysis showed that the direct and indirect comparisons of each node did not differ (P>0.05), and the consistency model was used for convergence. To rank the treatments, we used the surface under the cumulative ranking probabilities (SUCRA). A comparison-adapted funnel plot was used to assess the presence of small-written report result and publication bias.

Results

Characteristics of eligible studies

Fig 1 shows the literature retrieval process. After further discussing and considering the retrieved articles, 24 eligible manufactures[5,eight,10–31] were ultimately identified, and 64860 patients were included in this network meta-assay, with an average sample size of 2702.5 (range 54–12825). Amidst those studies, ix intervention-mensurate dosages for administering anti-D immunoglobulin were analyzed: 250 μg within 28 gestational weeks (antenatal 1/A), 300 μg within 28 gestational weeks (antenatal ii/B), 50 μg within 28 and 34 gestational weeks (antenatal 3/C), 100 μg between 28 and 34 gestational weeks (antenatal 4/D), 300 μg between 28 and 34 gestational weeks (antenatal v/East), placebo or blank control grouping (blank/F),100 μg ≤ dosage < 200 μg within 72 h postpartum (postnatal 1/G), 200 μg ≤ dosage < 300 μg within 72 h postpartum (postnatal 2/H), and 300 μg ≤ dosage < 500 μg within 72 h postpartum (postnatal three/I). All articles were written in good-quality English. Tabular array i summarizes the main characteristics of all included accomplice studies. Tabular array two has the handling abbreviations.

Period diagram of included studies.

Table 1

Main characteristics of all included studies.

First author	Year	Country	Sample size	I/C	Intervention	Control	Multivariate analysis	NOS
Ascari WQ	1968	America	1280	781/499	postnatal three/I	bare/F	YES	seven
Ascari WQ	1969	America	2876	1834/1042	postnatal three/I	blank/F	YES	viii
Bryant EC	1969	America	355	191/164	postnatal 3/I	blank/F	NO	8
Jennings ER	1968	Canada	493	258/235	postnatal 3/I	blank/F	NO	7
Pollack W	1968	America	1286	787/499	postnatal 3/I	blank/F	NO	eight
Robertson JG	1969	Scotland	212	100/112	postnatal iii/I	blank/F	NO	7
Stenchever MA	1971	America	54	26/28	postnatal 3/I	blank/F	NO	7
White CA	1970	America	5438	3784/1654	postnatal 3/I	blank/F	NO	8
Dudok D	1968	Holland	662	333/329	postnatal 3/I	blank/F	NO	ix
Clake CA	1968	England	197	95/102	postnatal 3/I	blank/F	NO	9
Buchanan DI	1969	Canada	430	223/207	postnatal2/H	postantal ane/Thousand	NO	9
Chown B	1969	Canada	2216	358/500;858/500	postnatal1/G; postantal3/I	blank/F	NO	viii
John GC	1969	Canada	202	65/42;53/42	postnatal1/G; postantal3/I	bare/F	NO	9
Tovey LA	1983	England	9178	3875/5303	antenatal 4/D	postantal one/Thousand	NO	seven
Huchet J	1987	French republic	1189	599/590	antenatal 4/D	postantal one/Thousand	YES	eight
Bowam JM	1987	Canada	12836	9303/3533	antenatal two/B	postantal 3/I	NO	6
Trolle B	1989	Kingdom of denmark	700	354/346	antenatal 2/B	postantal 2/H	NO	viii
Mayne South	1997	England	2851	1425/1426	antenatal 4/D	postantal 3/I	NO	9
Mackenzie IZ	1999	England	6466	3320/3146	antenatal iv/D	postantal three/I	NO	ix
Mackenzie IZ	2004	England	491	248/243	antenatal 2/B	postantal 3/I	NO	ix
Lee D	1995	England	1180	648/532	antenatal 3/C	blank/F	YES	8
Bowam JM	1978	Canada	2361	2109/252	antenatal 5/E	antenatal 2/B	NO	seven
Bowam JM	1978	Canada	2612	1598/1014	antenatal ii/B	postantal three/I	NO	7
Hermann M	1984	Sweden	9295	4895/4400	antenatal 1/A	postantal 2/H	NO	vii

Table ii

Treatment abbreviations.

Full proper name	Abbreviations
Administered 250 μg within 28 gestational weeks	antenatal one/A
Administered 300 μg inside 28 gestational weeks	antenatal 2/B
Administered 50 μg within 28 and 34 gestational weeks	antenatal iii/C
Administered 100 μg between 28 and 34 gestational weeks	antenatal 4/D
Administered 300 μg betwixt 28 and 34 gestational weeks	antenatal 5/Due east
Placebo or blank command group	blank/F
Administered 100 μg ≤ dosage < 200 μg within 72 h postpartum	postnatal 1/G
Administered 200 μg ≤ dosage < 300 μg within 72 h postpartum	postnatal two/H
Administered 300 μg ≤ dosage < 500 μg within 72 h postpartum	postnatal iii/I

Network meta-assay results

Network relationship and inconsistency examination. In this network meta-assay, the association between various anti-D immunoglobulin strategies and their clinical value in HDFN was analyzed for 24 cohort studies comprising 64860 patients and nine treatment measures. Fig 2 shows the network human relationship among the different treatment measures. Nodes are proportional to the number of patients included in the corresponding treatments, and edges are weighted according to the number of studies included in the corresponding comparisons. 9 treatment measures formed 3 triangles and two quadrilateral airtight loops. The inconsistency factor was obtained nether the inconsistency model using Gemetc software. Fig 3 shows the inconsistency plot used to identify heterogeneity amongst studies in the airtight loop of this network meta-analysis. Iii triangular loops and two quadratic loops are present in the network meta-analysis. The results showed that the inconsistency factor (IF) was 0.eleven ≤ 2.13, and the 95% confidence interval (CI) contained 0, suggesting that statistical inconsistency may not exist amongst these five closed loops (Fig 3). Furthermore, node analysis was used to clarify the differences betwixt direct and indirect comparisons among treatment measures (Table iii). P>0.05 indicates that no statistical inconsistencies were observed, suggesting that a network meta-analysis can be accomplished by directly or indirectly comparing dissimilar therapeutic measures. Thus, data on various handling measures can be converged using consistency models.

Network relationship of the included treatment measures.

Tabular array 3

Node assay.

Node analysis results
Side	Direct		Indirect		Difference		P>z
	Coef.	Std. Err.	Coef.	Std. Err.	Coef.	Std. Err.
A H	0.863	0.429	-1.012	42.161	1.874	42.163	0.965
B E	-2.123	2.001	5.147	3110.084	-seven.269	3110.085	0.998
B H	ii.605	ane.47	3.023	0.637	-0.417	1.602	0.794
B I	one.852	0.218	one.435	1.587	0.417	1.602	0.794
C F	1.899	0.239	half-dozen.653	203.357	-4.754	203.357	0.981
D 1000	1.441	0.314	1.876	0.905	-0.435	0.958	0.65
D I	0.989	0.297	0.555	0.911	0.435	0.958	0.65
F Thou	-3.269	0.974	-2.678	0.465	-0.591	1.061	0.578
F H	-1.791	0.631	-3.259	0.998	i.468	1.181	0.214
F I	-3.377	0.237	-2.351	i.068	-ane.026	1.102	0.352
Yard H	-0.773	1.229	1.039	0.724	-ane.812	ane.426	0.204
Yard I	-0.339	i.418	-0.556	0.401	0.218	1.473	0.882

Results of the Bayesian network meta-analysis. According to the network of comparisons (Tabular array four), the antenatal 5/E, antenatal 2/B, antenatal 4/D, antenatal i/A, postnatal 3/I, postnatal 2/H, and antenatal iii/C regimens significantly reduced the serum anti-D antibody-positive rates compared with that of the blank/F regimen alone (antenatal five/East vs. blank/F: OR = 0.00, 95% CI = 0.00–0.04; antenatal 2/B vs. blank/F: OR = 0.01, 95% CI = 0.00–0.01; antenatal 4/D vs. blank/F: OR = 0.01, 95% CI = 0.01–0.03; antenatal 1/A vs. blank/F: OR = 0.05, 95% CI = 0.01–0.18; postnatal 3/I vs. blank/F: OR = 0.04, 95% CI = 0.02–0.06, P<0.05; postnatal two/H vs. blank/F: OR = 0.11, 95% CI = 0.04–0.31; antenatal 3/C vs. blank/F: OR = 0.15, 95% CI = 0.09–0.24; all P<0.05). This indicated that injections of anti-D immunoglobulin, whether before or after delivery, significantly reduced the incidence of maternal serum that was positive for anti-D antibody in Rh-negative mothers with Rh-positive fetuses. Moreover, antenatal v/Eastward, antenatal 2/B, antenatal 4/D, antenatal one/A and postnatal 3/I were the most effective treatment measures for reducing the incidence of maternal anti-D antibody positivity (antenatal 5/E vs. antenatal two/B: OR = 0.12, 95% CI = 0.00–half-dozen.05; antenatal two/B vs. antenatal 4/D: OR = 0.41, 95% CI = 0.20–0.82, P<0.05; antenatal 4/D vs. postnatal 3/I: OR = 0.39, 95% CI = 0.22–0.67, P<0.05; postnatal 3/I vs. antenatal ane/A: OR = 0.78, 95% CI = 0.20–three.08, P>0.05). Similarly, we used a woods plot to represent the network meta-analysis results (Fig 4). All immunization schemes were significantly more effective than was the blank command scheme (P<0.05).

Forest plot of the network meta-analysis.

Tabular array 4

Network meta-assay event.

postnatal three/I	3.04	1.72 (0.81,iii.66)	27.71 (17.66,43.50)	0.02 (0.00,0.98)	0.39 (0.22,0.67)	4.15	0.16 (0.x,0.24)	1.28 (0.32,5.08)
	(1.02,9.03)					(2.17,seven.94)
0.33 * (0.eleven,0.98)	postnatal two/H	0.56 (0.17,1.92)	ix.eleven (3.20,25.92)	0.01 (0.00,0.37)	0.13 (0.04,0.41)	1.36	0.05 (0.02,0.16)	0.42 (0.eighteen,0.98)
						(0.43,4.29)
0.58 (0.27,i.24)	one.77	postnatal ane/Thou	xvi.14 (vii.00,37.22)	0.01 (0.00,0.61)	0.23 (0.13,0.40)	2.42	0.09 (0.04,0.22)	0.75 (0.17,iii.30)
	(0.52,vi.02)					(0.93,6.29)
0.04 * (0.02,0.06)	0.11*	0.06 * (0.03,0.14)	Blank/F	0.00 (0.00,0.04)	0.01 (0.01,0.03)	0.15	0.01 (0.00,0.01)	0.05 (0.01,0.18)
	(0.04,0.31)					(0.09,0.24)
52.84 * (ane.02,2730.18)	160.72 * (2.70,9562.99)	90.71 * (1.64,5031.73)	1464.44 * (27.65,77566.59)	antenatal 5/Due east	20.48 (0.38,1099.57)	219.16 (four.03,11931.17)	viii.35 (0.17,421.95)	67.86 (ane.05,4398.56)
2.58 * (one.48,4.48)	7.85 * (2.44,25.26)	4.43 * (2.48,vii.92)	71.49 * (35.95,142.eighteen)	0.05 (0.00,2.62)	antenatal four/D	10.seventy (4.66,24.57)	0.41 (0.twenty,0.82)	3.31 (0.78,13.98)
0.24 * (0.13,0.46)	0.73	0.41 (0.16,1.08)	6.68 * (iv.nineteen,10.67)	0.00 * (0.00,0.25)	0.09 * (0.04,0.21)	antenatal 3/C	0.04 (0.02,0.08)	0.31 (0.07,1.28)
	(0.23,two.31)
vi.33 * (4.15,ix.65)	xix.24 * (6.12,threescore.49)	ten.86 * (four.58,25.73)	175.29 * (94.99,323.46)	0.12 (0.00,vi.05)	ii.45 * (ane.22,iv.91)	26.23 * (12.14,56.lxx)	antenatal 2/B	8.12 (1.96,33.64)
0.78 (0.xx,3.08)	2.37*	1.34 (0.30,5.89)	21.58 * (5.64,82.53)	0.01 * (0.00,0.96)	0.xxx (0.07,1.27)	3.23	0.12 (0.03,0.51)	antenatal one/A
	(1.02,five.49)					(0.78,thirteen.37)

Rank probability. Injecting 300 μg of anti-D immunoglobulin at 28 and 34 gestational weeks (antenatal 5/East) was the most constructive handling (surface under the cumulative ranking curve [SUCRA] = 96.viii%; Fig 5), and administering 300 μg within 28 gestational weeks (antenatal 2/B) was the 2nd most effective (SUCRA = 89.2%). Administering no injection or a placebo was the to the lowest degree effective (SUCRA = 0.0%).

SUCRA for preventing maternal antibody sensitization.

Assessment of publication bias and small-sample effect detection. Fig half dozen shows the comparison-correction funnel plots of the included comparison. The funnel diagram is basically symmetric, and the regression line is less tilted; therefore, this study may have a small sample consequence and slight publication bias.

Discussion

In 2012, the National Institute of Wellness and Clinical Optimization (NICE) proposed that preventing maternal antibody sensitization via routine prenatal anti-D prophylaxis (RAADP) is a price-effective method (http://www.nice.org.uk/). The British Committee for Standards in Haematology (BCSH) published the latest guidelines in 2014, recommending the use of anti-D immunoglobulin to prevent haemolytic disease of the fetus and newborn [32]. These guidelines recommend that RAADP be performed in RhD-negative pregnant women in their third trimester of pregnancy. RAADP includes the following regimens: a unmarried dose of 300 μg (1500 IU) anti-D immunoglobulin between 28 and 30 gestational weeks or a two-dose regimen of 100 μg (500 IU) anti-D immunoglobulin at 28 and 34 gestational weeks. A Kleihauer-Betke test should be performed subsequently delivery to gauge whether fetomaternal hemorrhaging exceeded 4 ml, then another 100ug(500 IU) should be administered inside 72 hours of delivery. In 2017, the American College of Obstetricians and Gynecologists (ACOG)[33] recommends prophylactic anti-D immune globulin to unsensitized Rh D-negative women at 28 weeks of gestation. After birth, if the infant is Rh D positive, these mothers should receive anti-D immune globulin within 72 hours of birth.

However, an observational report noted that compliance with the unmarried injection regimen was better than that with the two-injection regimen[34]. A single injection may too reduce costs. No evidence exists to assess the efficacy of these therapeutic strategies[32].

Therefore, we conducted a network meta-analysis comparing multiple treatment measures. The results revealed that the antenatal 5/E, antenatal two/B, antenatal 4/D, antenatal one/A, postnatal 3/I, postnatal 2/H and antenatal 3/C regimens significantly reduced serum anti-D antibody positive rates compared with that of the bare/F regimen alone, indicating that anti-D immunoglobulin immunotherapy, whether administered before or after delivery, significantly reduced the incidence of maternal serum anti-D antibody positivity in Rh-negative mothers with Rh-positive fetuses. Moreover, antenatal five, antenatal 2, antenatal 4, antenatal 1 and postnatal 3 were the most constructive treatment measures for reducing the incidence of maternal anti-D antibiotic positivity. Therapeutic regimens antenatal 5 and antenatal 2 were likely the virtually effective regimens for preventing hemolytic diseases in fetuses and newborns.

The SUCRA for preventing maternal antibiotic sensitization indicated that the 300-μg anti-D immunoglobulin injection at 28 and 34 gestational weeks (antenatal 5/E) was likely the near constructive regimen (SUCRA = 96.8%), and administering 300 μg within 28 gestational weeks (antenatal two/B) was likely the second well-nigh effective (SUCRA = 89.2%). Administering no injection or a placebo was the least effective regimen (SUCRA = 0.0%). The anti-D immunoglobulin mechanism of activeness, which is closely related to the drug duration and dose, may explain these results. Anti-D immunoglobulin is extracted from the serum and used to prevent neonatal hemolysis.

RhD-positive ruby-red blood cells (containing the D antigen) from the fetus stimulate antibody production in RhD-negative mothers. During pregnancy and delivery of the first RhD-positive fetus to RhD-negative mothers, the red blood cells of the RhD-positive fetuses enter the RhD-negative mothers and stimulate the mothers to produce IgG anti-D antibodies. When an RhD-negative mother later carries an RhD-positive fetus, the antibodies in the maternal serum enter the fetal claret circulation via the placental barrier and can cause neonatal hemolysis.

However, during the pregnancy with the first RhD-positive fetus, or inside 72 hours after delivery, RhD-negative mothers tin exist intramuscularly injected with 300 μg anti-D immunoglobulin, which can bind to the D antigen leaked into the mother's serum and desensitize information technology, thus blocking anti-D antibody production in the mother'south serum. Anti-D immunoglobulin had no significant preventive consequence on mothers who had already produced anti-D antibodies.

Twenty-five micrograms (125 IU) of anti-D immunoglobulin tin typically protect confronting a fetal-maternal hemorrhage (FMH) of approximately i–2 ml of claret. Therefore, 100 μg (500 IU) of anti-D antibody tin can prevent an FMH of approximately 8 ml, and 300 μg tin can preclude an FMH of approximately thirty ml. An FMH of greater than 30 ml is uncommon [35]. However, pharmacokinetic studies take shown that anti-RhD levels vary among patients, and some may accept insufficient anti-RhD levels during childbirth [36]. A single injection of 300 μg anti-D immunoglobulin maintained a high immunopreventive result for approximately 12 weeks. Bowman et al. [37]suggested that women who failed to give birth within 12 weeks after receiving the prenatal doses should receive a second dose of anti-D immunoglobulin to maintain the immunopreventive effect.

Routine prenatal prophylaxis with anti-D immunoglobulin is unlikely to do good the electric current pregnancy or improve pregnancy outcomes, but information technology tin reduce the anti-D antibody product during subsequent pregnancies. Chilcott et al.[38]noted that routine anti-D immunoglobulin injections should prevent hereafter hemolytic diseases in infants. In many countries, including the Great britain and Commonwealth of australia, the guidelines recommend routine universal prenatal anti-D immunoglobulin prevention (http://www.ranzcog.edu.au/ and http://www.rcog.org.united kingdom of great britain and northern ireland/). The incidence of D-negative individuals varies amid indigenous groups, with the highest existence in Basques (xxx% -35%), followed by North American and European Caucasians (15%) [38]. In China, RhD-negative individuals found approximately 0.3% of the population [39]. Routine use of anti-D immunoglobulin is the main method of decreasing the erythrocyte alloimmunity ratio.

Conclusions

Several limitations must be considered when interpreting the results of this meta-analysis. Outset, the literature included in this written report spanned a long time period, and the titer or quality of anti-D immunoglobulin varies over fourth dimension, which may bear upon the result. 2nd, the recruited participants were all from western countries, and no studies could exist constitute regarding Asians and anti-D immunoglobulin. This might limit the awarding of our conclusions, and research on other races should be conducted.

In conclusion, this study showed that the electric current first-line recommendation is two 300-μg prenatal immunizations at 28 and 34 gestational weeks. If the anti-D immunoglobulin supply is inadequate, the 2nd culling should be a single 300-μg prenatal immunization at 28 gestational weeks.

Supporting data

S1 Checklist

PRISMA NMA checklist of Items to include when reporting a systematic review involving a network meta-analysis.

(DOCX)

S1 Table

The raw data of all included studies.

(XLSX)

Funding Statement

The author(south) received no specific funding for this work.

Data Availability

All relevant data are within the manuscript and its Supporting Information files.

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Decision Letter 0

28 Jan 2020

PONE-D-19-24055

Clinical value of unlike anti-D immunoglobulin strategies for preventing Rh hemolytic disease of the fetus and newborn: A network meta-analysis

PLOS One

Dear Mr Zhang,

Cheers for submitting your manuscript to PLOS 1. Afterwards conscientious consideration, nosotros feel that information technology has merit but does not fully run across PLOS Ane's publication criteria every bit information technology currently stands. There were several major comments and concerns raised during the review of your manuscript. Therefore, we invite you to submit a revised version of the manuscript that addresses ALL of the points raised during the review procedure.

We would appreciate receiving your revised manuscript by Mar 12 2020 11:59PM. When yous are set up to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

If y'all would like to make changes to your financial disclosure, please include your updated statement in your cover alphabetic character.

To enhance the reproducibility of your results, we recommend that if applicative you eolith your laboratory protocols in protocols.io, where a protocol tin can be assigned its own identifier (DOI) such that it can be cited independently in the time to come. For instructions encounter: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

Please include the following items when submitting your revised manuscript:

• A rebuttal letter that responds to each indicate raised by the academic editor and reviewer(south). This letter of the alphabet should exist uploaded as separate file and labeled 'Response to Reviewers'.

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Please note while forming your response, if your article is accustomed, yous may have the opportunity to make the peer review history publicly available. The record will include editor conclusion letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.

We look forward to receiving your revised manuscript.

Kind regards,

Frank T. Spradley

Academic Editor

PLOS I

Journal requirements:

When submitting your revision, we need you lot to address these additional requirements:

1. Delight ensure that your manuscript meets PLOS One's style requirements, including those for file naming. The PLOS ONE mode templates can be institute at http://www.plosone.org/attachments/PLOSOne_formatting_sample_main_body.pdf and http://www.plosone.org/attachments/PLOSOne_formatting_sample_title_authors_affiliations.pdf

two. Please upload a new copy of Figure ii as the detail is not clear. Please follow the link for more than data: http://blogs.PLOS.org/everyone/2011/05/ten/how-to-cheque-your-manuscript-epitome-quality-in-editorial-manager/

3. Delight include your tables every bit part of your main manuscript and remove the individual files. Please note that supplementary tables (should remain/ be uploaded) as divide "supporting information" files

4. . Nosotros note you take included ii unlike tables in your manuscript labelled as Table three; 'Table iii Treatment abbreviations' and 'Table iii Network meta-analysis upshot'. Please review these and ensure that y'all refer to all tables in the text of your manuscript so that they tin exist separately identified; if accepted, production will demand this reference to link the reader to each Table.

Reviewers' comments:

Reviewer'south Responses to Questions

Comments to the Author

1. Is the manuscript technically audio, and do the data back up the conclusions?

The manuscript must describe a technically sound piece of scientific enquiry with information that supports the conclusions. Experiments must accept been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

**********

2. Has the statistical assay been performed appropriately and rigorously?

Reviewer #1: Yes

**********

iii. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully bachelor without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as office of the manuscript or its supporting data, or deposited to a public repository. For example, in addition to summary statistics, the data points backside means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a tertiary political party—those must be specified.

Reviewer #1: Yes

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS One does non copyedit accepted manuscripts, so the linguistic communication in submitted articles must exist clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, and then please notation any specific errors here.

Reviewer #one: Yeah

**********

five. Review Comments to the Writer

Reviewer #1: The authors investigated the various anti-d immunoglobulin strategies used for prevention of Rh hemolytic affliction of the fetus and newborn using a network meta-analysis. Of the 9 therapeutic measures studied, they found that giving 300 µg anti-D immunoglobulin at 28 and 34 weeks of gestation was the most constructive measure for preventing maternal antibody sensitization, followed past a single injection at 28 weeks of gestation. This is interesting work clearly written.

Reviewer's comments;

ane. Page 3 (Results, last sentence): Suggest adding - Table 2 has the treatment abbreviations.

two. Page five (Table ii): This table was incorrectly labeled every bit Table 3. Delight correct.

three. Page ix (Word, centre of commencement paragraph): Suggest calculation 100 µg to the sentence that states that …then another 500 IU should be administered…

four. Page 9 (Discussion, first paragraph): ACOG is the American College of Obstetricians and Gynecologists. Please correct.

five. Page nine (Discussion, first paragraph): The sentence …(ACOG) recommended a single injection of 300 µg anti-D immunoglobulin at 28 weeks of pregnancy with an RhD–positive baby, then another injection of 300 µg over again after nativity… should be corrected as information technology is disruptive equally written. ACOG recommends safe anti-D immune globulin to unsensitized Rh D-negative women at 28 weeks of gestation. Afterwards nascency, if the baby is Rh D positive, these mothers should receive anti-D immune globulin within 72 hours of birth.

6. Page 10 (Word, top paragraph, first line): The area in parenthesis later on …anti-D antibiotic positive rates compared with that of the bare/F regimen alone… can exist deleted as information technology already appears in the Results section.

vii. Folio 10 (Discussion, top paragraph, line 10): Similarly as in #6 above, the area in parenthesis later on …incidence of maternal anti-D positivity…can be deleted.

eight. Page 11 (Give-and-take, next to last paragraph, last 4 lines): Please clarify what y'all mean by …but few studies have focused on the first fetus born to RhD-negative mothers. Supply references of the few studies. As well, please reference the last sentence …Some studies have likewise plant that using anti-D immunoglobulin may cause hemolysis in fetuses during pregnancy.

**********

vi. PLOS authors take the pick to publish the peer review history of their article (what does this mean?). If published, this volition include your full peer review and any attached files.

If yous choose "no", your identity volition remain anonymous only your review may nevertheless be made public.

Practise you lot desire your identity to be public for this peer review? For data about this pick, including consent withdrawal, please see our Privacy Policy.

Reviewer #i: No

[Note: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Delight log into your business relationship, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files to exist viewed.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (Footstep) digital diagnostic tool, https://pacev2.apexcovantage.com/. Pace helps ensure that figures run across PLOS requirements. To use PACE, you lot must first register every bit a user. Registration is free. So, login and navigate to the UPLOAD tab, where you volition find detailed instructions on how to use the tool. If y'all encounter any problems or take whatsoever questions when using Stride, please electronic mail us at gro.solp@serugif. Please note that Supporting Information files practise not demand this step.

Author response to Decision Letter of the alphabet 0

1 Feb 2020

Dear reviewers:

I am very grateful to your comments for the manuscript. Co-ordinate with your advice, nosotros amended the relevant part in manuscript. Some of your questions were answered below.

--------------------------------------------------------------------

Journal requirements:

i. Please ensure that your manuscript meets PLOS ONE's way requirements, including those for file naming. The PLOS Ane style templates can be found at http://world wide web.plosone.org/attachments/PLOSOne_formatting_sample_main_body.pdf and http://www.plosone.org/attachments/PLOSOne_formatting_sample_title_authors_affiliations.pdf

The authors' respond: the manuscript has been revised equally PLOS I's style requirements

2. Delight upload a new copy of Effigy 2 every bit the detail is non articulate. Please follow the link for more information: http://blogs.PLOS.org/everyone/2011/05/10/how-to-cheque-your-manuscript-image-quality-in-editorial-manager/

The authors' answer: The new Effigy 2 has been repalced.

3. Delight include your tables every bit role of your chief manuscript and remove the individual files. Please note that supplementary tables (should remain/ exist uploaded) as split "supporting information" files

The authors' respond: The tables has been inclued in the manuscript.There is no supplementary tables.

4. We annotation you lot have included two different tables in your manuscript labelled as Table iii; 'Table 3 Treatment abbreviations' and 'Tabular array 3 Network meta-assay outcome'. Please review these and ensure that you refer to all tables in the text of your manuscript so that they can be separately identified; if accustomed, production will need this reference to link the reader to each Table.

The authors' answer: Tabular array label has been modified .Table 3 Treatment abbreviations has been replaced by Table ii Treatment abbreviations.

Review Comments to the Author

Reviewer #1: The authors investigated the various anti-d immunoglobulin strategies used for prevention of Rh hemolytic disease of the fetus and newborn using a network meta-analysis. Of the nine therapeutic measures studied, they plant that giving 300 µg anti-D immunoglobulin at 28 and 34 weeks of gestation was the most constructive measure for preventing maternal antibody sensitization, followed by a single injection at 28 weeks of gestation. This is interesting piece of work clearly written.

Reviewer's comments;

one. Page 3 (Results, final sentence): Suggest adding - Table 2 has the handling abbreviations.

The authors' answer: The sentence has been added.

2. Page 5 (Table 2): This table was incorrectly labeled as Table 3. Delight correct.

The authors' answer: The Table label has been corrected.

3. Folio 9 (Discussion, middle of kickoff paragraph): Suggest adding 100 µg to the judgement that states that …then another 500 IU should be administered…

The authors' answer: The "100 µg" has been added in the sentence.

4. Folio 9 (Discussion, showtime paragraph): ACOG is the American College of Obstetricians and Gynecologists. Please right.

The authors' respond: "American Association of Obstetricians and Gynecologists" has been replaced past "American College of Obstetricians and Gynecologists".

5. Page 9 (Discussion, first paragraph): The sentence …(ACOG) recommended a single injection of 300 µg anti-D immunoglobulin at 28 weeks of pregnancy with an RhD–positive baby, and so some other injection of 300 µg again after birth… should be corrected as information technology is confusing as written. ACOG recommends condom anti-D immune globulin to unsensitized Rh D-negative women at 28 weeks of gestation. Afterwards nascency, if the baby is Rh D positive, these mothers should receive anti-D allowed globulin within 72 hours of nascency.

The authors' respond: The confusing judgement has been revised.

6. Page 10 (Give-and-take, top paragraph, outset line): The area in parenthesis after …anti-D antibody positive rates compared with that of the blank/F regimen alone… can be deleted equally it already appears in the Results department.

The authors' answer: The area in parenthesis has been deleted.

7. Folio 10 (Discussion, top paragraph, line 10): Similarly as in #6 above, the area in parenthesis subsequently …incidence of maternal anti-D positivity…can be deleted.

The authors' answer: The area in parenthesis has been deleted.

8. Page 11 (Discussion, adjacent to concluding paragraph, last four lines): Please clarify what you mean by …simply few studies have focused on the get-go fetus born to RhD-negative mothers. Supply references of the few studies. Likewise, please reference the last judgement …Some studies have also institute that using anti-D immunoglobulin may cause hemolysis in fetuses during pregnancy.

The authors' answer: Confused sentences have been deleted.

--------------------------------------------------------------------

We acknowledge the reviewer'due south comments and suggestions very much, which are valuable in improving the quality of our manuscript.

Sincerely yours,

Xiaohui Xie1;Yi Zhang2

one.Department of Obstetrics and Gynecology，the Start People's Hospital of Neijiang,Neijiang 641000,Sichuan Province, P. R. China2．Section of General Surgery，the First People's Hospital of Neijiang,Neijiang 641000,Sichuan Province, P. R. People's republic of china

January xxx, 2020

Attachment

Submitted filename: Response to Reviewers.doc

Decision Letter 1

xiii February 2020

PONE-D-19-24055R1

Clinical value of different anti-D immunoglobulin strategies for preventing Rh hemolytic disease of the fetus and newborn: A network meta-analysis

PLOS ONE

Dear Mr Zhang,

Give thanks you for submitting your manuscript to PLOS One. After careful consideration, we feel that information technology has merit but does not fully meet PLOS Ane'south publication criteria as it currently stands. There are two boosted comments from the reviewer that must exist addressed. Therefore, nosotros invite you lot to submit a revised version of the manuscript that addresses the points raised during the review procedure.

Nosotros would appreciate receiving your revised manuscript by Mar 29 2020 11:59PM. When y'all are ready to submit your revision, log on to https://world wide web.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter.

To heighten the reproducibility of your results, nosotros recommend that if applicable you lot deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the time to come. For instructions meet: http://journals.plos.org/plosone/southward/submission-guidelines#loc-laboratory-protocols

Please include the post-obit items when submitting your revised manuscript:

• A rebuttal letter that responds to each bespeak raised by the academic editor and reviewer(southward). This letter of the alphabet should be uploaded as separate file and labeled 'Response to Reviewers'.

• A marked-up copy of your manuscript that highlights changes made to the original version. This file should exist uploaded as divide file and labeled 'Revised Manuscript with Track Changes'.

• An unmarked version of your revised paper without tracked changes. This file should exist uploaded equally carve up file and labeled 'Manuscript'.

Delight note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor determination letters (with reviews) and your responses to reviewer comments. If eligible, we will contact y'all to opt in or out.

We look forrard to receiving your revised manuscript.

Kind regards,

Frank T. Spradley

Bookish Editor

PLOS Ane

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and y'all feel that this manuscript is now acceptable for publication, yous may indicate that here to bypass the "Comments to the Author" section, enter your conflict of interest argument in the "Confidential to Editor" section, and submit your "Accept" recommendation.

Reviewer #1: (No Response)

**********

2. Is the manuscript technically audio, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn accordingly based on the data presented.

Reviewer #ane: Yep

**********

3. Has the statistical assay been performed appropriately and rigorously?

Reviewer #i: Yes

**********

4. Have the authors made all information underlying the findings in their manuscript fully bachelor?

The PLOS Data policy requires authors to brand all information underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points backside means, medians and variance measures should be bachelor. If there are restrictions on publicly sharing data—e.g. participant privacy or employ of data from a third party—those must exist specified.

Reviewer #1: Yep

**********

5. Is the manuscript presented in an intelligible manner and written in standard English?

PLOS 1 does not copyedit accepted manuscripts, then the linguistic communication in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yep

**********

6. Review Comments to the Writer

Delight employ the space provided to explain your answers to the questions above. Y'all may besides include additional comments for the author, including concerns well-nigh dual publication, enquiry ethics, or publication ideals. (Delight upload your review equally an attachment if information technology exceeds twenty,000 characters)

Reviewer #one: The investigators take addressed previous comments and have made changes to the manuscript. Still, I have ii additional comments:

1. Results of the Bayesian network meta-assay (lines half dozen-vii): Based on Table 4, the results for postnatal 3/I vs blank/F should be OR=0.04, 95% CI=0.02-0.06. Delight clarify.

2. Figure v: The labeling of the various curves should be reevaluated. For instance, antenatal v/E had a SUCRA of 96.8%, even so the Figure has antenatal ane with that SUCRA. Antenatal 2/B had a SUCRA of 89.2%, nonetheless the Figure has antenatal 3 with that SUCRA.

**********

7. PLOS authors have the option to publish the peer review history of their commodity (what does this mean?). If published, this volition include your full peer review and any attached files.

If y'all cull "no", your identity volition remain anonymous but your review may even so be made public.

Practice you want your identity to be public for this peer review? For information about this pick, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

[Notation: If reviewer comments were submitted as an zipper file, they will be attached to this email and accessible via the submission site. Delight log into your account, locate the manuscript record, and check for the activeness link "View Attachments". If this link does not appear, there are no attachment files to be viewed.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (Step) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To utilize PACE, yous must outset annals as a user. Registration is gratis. Then, login and navigate to the UPLOAD tab, where you will notice detailed instructions on how to utilise the tool. If you meet any issues or have any questions when using PACE, please e-mail u.s.a. at gro.solp@serugif. Delight note that Supporting Information files do not need this pace.

Writer response to Determination Letter 1

18 Feb 2020

Reviewer #1: The investigators have addressed previous comments and have made changes to the manuscript. Nevertheless, I have 2 additional comments:

i. Results of the Bayesian network meta-assay (lines 6-7): Based on Table 4, the results for postnatal 3/I vs blank/F should be OR=0.04, 95% CI=0.02-0.06. Please clarify.

Respond: the results for postnatal iii/I vs blank/F has been revised.

2. Figure 5: The labeling of the diverse curves should be reevaluated. For example, antenatal 5/Due east had a SUCRA of 96.eight%, all the same the Figure has antenatal 1 with that SUCRA. Antenatal ii/B had a SUCRA of 89.2%, however the Figure has antenatal 3 with that SUCRA.

Answer:The labeling of the various curves has been reevaluated.The Figure 5 has been replaced.

Supporting Information files and PRISMA checklist are uploaded.please check

Zipper

Submitted filename: Response to Reviewers.md

Decision Letter ii

21 Feb 2020

Clinical value of different anti-D immunoglobulin strategies for preventing Rh hemolytic disease of the fetus and newborn: A network meta-analysis

PONE-D-nineteen-24055R2

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Credence letter

26 February 2020

PONE-D-nineteen-24055R2

Clinical value of different anti-D immunoglobulin strategies for preventing Rh hemolytic disease of the fetus and newborn: A network meta-analysis

Dear Dr. Zhang:

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Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7067404/